Abstract Chronic pain is a complex problem affecting over a billion people worldwide. An important goal for basic scientists is to develop and test treatments in animals that can be translated for use in chronic pain patients. Chronic pain patients suffer both because of the pain and the disruption of daily life routines (e.g., exercise, socializing). The development of treatments that restore normal activity will require the use of pain tests that mimic these effects. Most preclinical models of pain assess an animal's response to a noxious stimulus. Such pain-stimulated tests are useful in revealing whether a stimulus is noxious, but do not mimic the disruptive effects of pain on activity. Our objective is to use suppression of home cage wheel running in rats as a model of pain-suppressed activity in humans. Wheel running is a natural rodent behavior that requires no training other than placing a running wheel in the rat's home cage. Although a number of pain-suppressed tests have been developed including suppression of wheel running, home cage wheel-running could be a particularly useful model because wheel-running is a natural rodent behavior, assessment takes place in the rat's home cage (a low-stress environment), and measurements can be taken 24 hours a day. The proposed studies will reveal whether wheel-running is an accurate measure of clinical pain by testing rats with inflammatory and migraine pain. Five specific hypotheses will be tested: 1) Inflammatory and migraine pain will suppress wheel-running; 2) The affective dimension of inflammatory pain measured with wheel running will recover prior to noxious stimuli evoked responses; 3) Administration of pain treatments will restore pain-suppressed wheel running; 4) Wheel-running will distinguish between the antinociceptive (increased wheel running) and side effects (decreased wheel running) of drug treatments; and 5) Female rats will be more sensitive than male rats to pain-suppressed wheel running. These hypotheses will be tested by monitoring wheel- running in the home cage of male and female rats before and after administration of Complete Freund's Adjuvant (CFA) in the right hindpaw to induce inflammatory pain or administration of a TRPA1 agonist onto the dura mater to induce migraine pain. Wheel running will be assessed 23 hours a day for at least 7 days. Rats will be removed once a day to assess pain-evoked behavior (von Frey and Hargreaves tests) and to administer drugs (CFA, ketoprofen, morphine, amphetamine, sumatriptan). These studies will reveal whether pain-suppressed wheel running is a reliable measure of nociception and a valid model of pain-suppressed behavior in humans. Given the need to develop novel analgesics and improve upon existing preclinical pain assays, the proposed studies could provide a significant advance in pain research.